INVESTIGATIONS INTO PHENOTYPE & GENOTYPE OF ATYPICAL PRIMARY HYPEROXALURIA

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The causesof hyperoxaluria are manyfold. The spectrum of its clinical manifestations encompasses the more benign conditions such as idiopathic hyperoxaluria to the more malignant syndromes of primary hyperoxaluria. In primary hyperoxaluria, deficiencies of hepatic enzymes involved in oxalate metabolism, inherited in an autsomal recessive manner, lead to accumulation of oxalate. The phenotypic expression of the marked oxalate overproduction in these disorders is oxalate nephrolithiasis, progressive renal failure and systemic oxalosis. primary hyperoxaluria type I is characterized by a defect of liver-specific alanine-glyoxylate transaminase (AGT). In primary hyperoxaluria type II there is an absence of either gyoxylate reductase (GR) and/or glycerate dehydrogenase (GDH). Since the availability of immunocytologic enzymatic evaluation of human liver biopsy specimens, a subgroup of patients with similar phenotypic features (marked hyperoxaluria with nephrolithiasis) but with normal AGT and GDH levels has been identified (atypical hyperoxaluria). The etiology of the excessive renal oxalate is one possible cause. Metabolic overproduction due to an yet undefined hepatic enzyme pathway is another possible cause. We propose to measure enteric oxalate absorption in patients with atypical hyperoxaluria. The six previously identified families of the Mayo Clinic experience will serve as study subjects and compared to healthy adults and age-matched control subjects. An especially prepared oxalate meal consisting of 20 mg of 13c-labeled oxalate will be ingested and urinary 13c-oxalate excretion measured via gas chromatography/mass spectroscopy. Since the majority of oxalate that is absorbed from the gut can be recovered in the urine, i.e., it is neither catabolized nor absorbed, urinary oxalate levels are useful markers for exogenously-derived oxalate. If enteric hyperabsorption is found in these patients, future inquiry can be directed towards discovering pathways of oxalate absorption in the GI tract thus targeting potential life-chaging interventions.